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Details

Stereochemistry ACHIRAL
Molecular Formula C32H29N5O2
Molecular Weight 515.605
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ENZASTAURIN

SMILES

CN1C=C(C2=C1C=CC=C2)C3=C(C(=O)NC3=O)C4=CN(C5CCN(CC6=CC=CC=N6)CC5)C7=C4C=CC=C7

InChI

InChIKey=AXRCEOKUDYDWLF-UHFFFAOYSA-N
InChI=1S/C32H29N5O2/c1-35-19-25(23-9-2-4-11-27(23)35)29-30(32(39)34-31(29)38)26-20-37(28-12-5-3-10-24(26)28)22-13-16-36(17-14-22)18-21-8-6-7-15-33-21/h2-12,15,19-20,22H,13-14,16-18H2,1H3,(H,34,38,39)

HIDE SMILES / InChI

Molecular Formula C32H29N5O2
Molecular Weight 515.605
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Originator

Curator's Comment: # Eli Lilly

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
1310 ng/mL
700 mg 1 times / day steady-state, oral
dose: 700 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ENZASTAURIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
17400 ng × h/mL
700 mg 1 times / day steady-state, oral
dose: 700 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ENZASTAURIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
14.4 h
700 mg 1 times / day steady-state, oral
dose: 700 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
ENZASTAURIN plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
5%
ENZASTAURIN plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Hypoxia, tumor endothelium, and targets for therapy.
2005
The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts.
2005 Aug 15
Perspectives in central nervous system malignancies.
2006 Jun
Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer.
2006 Sep 1
Inorganic pyrophosphate generation by transforming growth factor-beta-1 is mainly dependent on ANK induction by Ras/Raf-1/extracellular signal-regulated kinase pathways in chondrocytes.
2007
Survival improvement in thoracic cancer: progress from the last decade and beyond.
2007 Aug
Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer.
2007 Aug 1
Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors.
2007 Feb
Safety, tolerability, QTc evaluation, and pharmacokinetics of single and multiple doses of enzastaurin HCl (LY317615), a protein kinase C-beta inhibitor, in healthy subjects.
2007 Sep
Chemoradiotherapy in malignant glioma: standard of care and future directions.
2007 Sep 10
Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Conclusion.
2008
Protein kinase C isozymes as therapeutic targets for treatment of human cancers.
2008
Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs.
2008 Aug 5
A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.
2008 Jan
Targeted treatment and new agents in diffuse large B-cell lymphoma.
2008 Jul
The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines.
2008 Jul
[Protein kinases C: a new cytoplasmic target].
2008 Jul-Aug
Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C.
2008 Jun
Involvement of protein kinase C beta-extracellular signal-regulating kinase 1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion.
2008 Mar
[Recent therapeutic progress in non-Hodgkin lymphoma: focusing on diffuse large B-cell lymphoma and follicular lymphoma].
2008 Oct
Novel therapies in breast cancer: what is new from ASCO 2008.
2008 Oct 1
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells.
2008 Sep 2
The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells.
2008 Sep 8
Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.
2009
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.
2009 Feb 12
Antiangiogenic drugs in ovarian cancer.
2009 Jan 13
[Role of PKCbeta in the malignant tumors and enzastaurin, a PKCbeta inhibitor].
2009 May
A phase I trial of enzastaurin in patients with recurrent gliomas.
2009 May 15
Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths.
2009 May 28
Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70.
2010 Jan
Protein kinase Cbeta modulates ligand-induced cell surface death receptor accumulation: a mechanistic basis for enzastaurin-death ligand synergy.
2010 Jan 8
Patents

Sample Use Guides

1125 mg loading dose then 500 mg, oral, daily, until disease progression or maximum of 3 years
Route of Administration: Oral
In the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 uM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin.
Substance Class Chemical
Created
by admin
on Mon Mar 31 18:26:16 GMT 2025
Edited
by admin
on Mon Mar 31 18:26:16 GMT 2025
Record UNII
UC96G28EQF
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ENZASTAURIN
INN   MI   WHO-DD  
INN   USAN  
Official Name English
LY-317615
Preferred Name English
ENZASTAURIN [MI]
Common Name English
Enzastaurin [WHO-DD]
Common Name English
LY317615
Code English
3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(PYRIDIN-2-YLMETHYL)PIPERIDIN-4-YL)-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE
Systematic Name English
enzastaurin [INN]
Common Name English
1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(2-PYRIDINYLMETHYL)-4-PIPERIDINYL)-1H-INDOL-3-YL)-
Systematic Name English
DB-102
Code English
ENZASTAURIN [USAN]
Common Name English
DB102
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 849821
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
FDA ORPHAN DRUG 277209
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
NCI_THESAURUS C2089
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
FDA ORPHAN DRUG 208505
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
Code System Code Type Description
INN
8426
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
PUBCHEM
176167
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
SMS_ID
100000127423
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
EPA CompTox
DTXSID5044029
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
ChEMBL
CHEMBL300138
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
USAN
HI-222
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
CAS
170364-57-5
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
WIKIPEDIA
ENZASTAURIN
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
EVMPD
SUB33466
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
FDA UNII
UC96G28EQF
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
MESH
C504878
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
DRUG BANK
DB06486
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
NCI_THESAURUS
C77392
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY
MERCK INDEX
m4926
Created by admin on Mon Mar 31 18:26:16 GMT 2025 , Edited by admin on Mon Mar 31 18:26:16 GMT 2025
PRIMARY Merck Index
Related Record Type Details
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
Related Record Type Details
ACTIVE MOIETY